Montelukast Sodium Oral Granules

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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1 DEFINITION

Montelukast Sodium Oral Granules contain Montelukast Sodium equivalent to NLT 90.0% and NMT 108.0% of the labeled amount of montelukast (C₃₅H₃₆CINO₃S).

[NOTE-Avoid exposure of samples containing montelukast to light.]

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 197U

Diluent: Methanol and water (3:1)

Standard solution: 3.3 µg/mL of USP Montelukast Dicyclohexylamine RS in Diluent

Sample stock solution: Nominally 0.02 mg/mL of montelukast prepared as follows. Transfer the contents of one packet to a suitable volumetric flask, add 66% of the flask volume of Diluent, shake well, and sonicate for 15 min with occasional shaking. Cool to room temperature, dilute with Diluent to volume, and mix well.

Sample solution: Nominally 2 µg/mL of montelukast in Diluent from the Sample stock solution. Pass a portion of the resulting solution through a suitable filter of 0.45-µm pore size or centrifuge to obtain a clear solution.

Wavelength range: 210-400 nm

Acceptance criteria: The Sample solution exhibits maxima only at the same wavelengths as the Standard solution.

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Diluent: Methanol and water (3:1)

Solution A: 0.2% (v/v) trifluoroacetic acid in water

Solution B: Methanol and acetonitrile (3:2)

Mobile phase: See Table 1.

Table 1

Standard solution: 0.33 mg/mL of USP Montelukast Dicyclohexylamine RS in Diluent

System suitability solution: Transfer 10 mL of the Standard solution to a clear 10-mL volumetric flask, add 4 µL of Hydrogen peroxide, and mix well. Expose the flask for at least 4 h to ambient light or 10 min to a 4 klx cool white light. [NOTE-Montelukast is partially converted to the cis-isomer under these conditions.]

Sensitivity solution: 0.33 µg/mL of USP Montelukast Dicyclohexylamine RS in Diluent from the Standard solution

Sample solution: Nominally 0.24 mg/mL of montelukast prepared as follows. Transfer the equivalent of 60 mg of montelukast from the contents of the packets (NLT 15) to a 500-mL volumetric flask, and add 250 mL of Diluent. Shake well and sonicate for 30 min, with occasional shaking. Pass a portion of the resulting solution through a suitable filter of 0.45-µm pore size or centrifuge to obtain a clear solution.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 255 nm

Columns

Guard: 3 - mm x 4 - mm packing L11

Analytical: 4.6-mm x 10-cm; 3-µm packing L11

Column temperature: 50°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

Run time: 2 times the retention time of montelukast

System suitability

Samples: Standard solution, System suitability solution, and Sensitivity solution [NOTE-The relative retention times for the cis-isomer and montelukast are about 0.92 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.5 between the cis-isomer and montelukast, System suitability solution

Relative standard deviation: NMT 2.0% for five injections, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) in the portion of Oral Granules taken:

                         Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) ×100

r_U = peak response from the Sample solution 

r_S = peak response from the Standard solution

C_S = concentration of USP Montelukast Dicyclohexylamine RS in the Standard solution (mg/mL)

C_U = nominal concentration of montelukast in the Sample solution (mg/mL)

M_r1 = molecular weight of montelukast, 586.18

M_r2 = molecular weight of montelukast dicyclohexylamine, 767.50

Acceptance criteria: 90.0%~108.0%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

4.1.1 Test 1

Medium: 0.5% (w/v) sodium dodecyl sulfate in water; 900 mL. Do not deaerate.

Apparatus 1: 100 mesh; 50 rpm

Time: 15 min

Solution A: 0.2% (v/v) trifluoroacetic acid in water

Solution B: 0.2% (v/v) trifluoroacetic acid in acetonitrile

Mobile phase: Solution A and Solution B (1:1)

Standard stock solution: 0.33 mg/mL of USP Montelukast Dicyclohexylamine RS in methanol (equivalent to 0.25 mg/ml. of montelukast)

Standard solution: (L/900) mg/ml. of montelukast in Medium from the Standard stock solution, where L is the label claim in mg/packet of montelukast

Sample solution: Place the entire contents of one packet in the basket. At the appropriate time point, pass a portion of the solution under test through a suitable filter to obtain a clear solution. Discard the first 10 mL of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 389 nm

Column: 3.0-mm x 10-cm; 5-µm packing L11

Column temperature: 50°

Flow rate: 0.9 mL/min

Injection volume: 25 µL

Run time: 1.5 times the retention time of montelukast

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) dissolved:

                         Result = (r_U/r_S) × C_S x V x (1/L) x 100

r_U = peak response of montelukast from the Sample solution

r_S = peak response of montelukast from the Standard solution

C_S = concentration of montelukast in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/packet)

Tolerances: NLT 85% (Q) of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) is dissolved.

4.1.2 Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: 0.5% (w/v) sodium dodecyl sulfate in water, 900 mL

Apparatus 1: 100 mesh; 50 rpm

Time: 15 min

Solution A: 0.07 g/L of monobasic sodium phosphate

Solution B: Acetonitrile

Mobile phase: Solution A and Solution B (45:55). Add 1.33 mL/L of triethylamine and adjust with phosphoric acid to a pH of 6.7.

Standard stock solution: 0.1 mg/mL of montelukast from montelukast sodium hydrate prepared as follows. Transfer a suitable amount of montelukast sodium hydrate to an appropriate volumetric flask. Dissolve in 4% of the flask volume of methanol and dilute with Medium to volume. Determine the water content of montelukast sodium hydrate at the time of use.

Standard solution: 0.004 mg/mL of montelukast in Medium from the Standard stock solution

Sample solution: Place the entire contents of one packet in the basket. At the appropriate time point, centrifuge a portion of the solution under test.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm x 5-cm; 1.8-µm packing L1

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 100 µL

Run time: 1.5 times the retention time of montelukast

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) dissolved:

                         Result = (r_U/r_S) × C_S x V x (1/L) x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of montelukast in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/packet)

Tolerances: NLT 80% (Q) of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) is dissolved.

4.1.3 Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: 0.5% (w/v) sodium dodecyl sulfate in water, 900 mL

Apparatus 2: 50 rpm

Time: 10 min

Solution A: 2.72 g/L of monobasic potassium phosphate in water

Mobile phase: Acetonitrile and Solution A (70:30)

Diluent: Acetonitrile and water (50:50)

System suitability solution: Expose a portion of Standard solution in a clear glass vial to direct room light for about 30 min.

Standard stock solution: 0.524 mg/mL of USP Montelukast Dicyclohexylamine RS in Diluent (equivalent to 0.4 mg/mL of montelukast)

Standard solution: 0.0065 mg/mL of USP Montelukast Dicyclohexylamine RS in Medium from the Standard stock solution (equivalent to 0.005 mg/mL of montelukast)

Sample solution: Transfer the entire contents of one packet to the dissolution vessel. At the specified time point, withdraw 10 mL of sample from the dissolution vessel. Pass a portion of the solution under test through a suitable filter. Discard the first 5 mL of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 281 nm

Column: 4.6-mm x 3-cm; 3-µm packing L1

Column temperature: 40°

Flow rate: 0.8 mL/min

Injection volume: 25 µL

Run time: About 1.5 times the retention time of montelukast

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for Z-isomer and montelukast are 0.8 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between the Z-isomer and montelukast, System suitability solution

Tailing factor: NMT 2.0 for montelukast, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) dissolved:

                         Result = (r_U/r_S) × C_S x V x (1/L) x (M_r1/M_r2) × 100

r_U = peak response from the Sample solution 

r_S = peak response from the Standard solution 

C_S = concentration of USP Montelukast Dicyclohexylamine RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/packet)

M_r1 = molecular weight of montelukast, 586.18

M_r2 = molecular weight of montelukast dicyclohexylamine, 767.50

Tolerances: NLT 80% (Q) of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) is dissolved.

4.1.4 Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium: 0.5% (w/v) sodium dodecyl sulfate in water: 900 mL

Apparatus 1: 100 mesh; 50 rpm

Time: 20 min

Solution A: 3.9 g/L of sodium phosphate monobasic dihydrate in water. Adjust with dilute phosphoric acid to a pH of 3.7.

Mobile phase: Acetonitrile and Solution A (80:20)

Diluent: Medium

Standard solution: 0.005 mg/mL of montelukast in Diluent from montelukast sodium hydrate. Determine the water content of montelukast sodium hydrate at the time of use.

Sample solution: Place the entire contents of one packet in the basket. At the specified time point, withdraw 10 mL of sample from the dissolution vessel. Pass a portion of the solution under test through a suitable filter paper. Discard the first 3 mL of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 15-cm; 5-µm packing L1

Temperatures

Autosampler: 20°

Column: 28°

Flow rate: 1.5 mL/min

Injection volume: 50 µL

Run time: NLT 1.5 times the retention time of montelukast

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for montelukast

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) dissolved:

                         Result = (r_U/r_S) × C_S x V x (1/L) x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of montelukast in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/packet)

Tolerances: NLT 80% (Q) of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) is dissolved.

Change to read:

4.2 UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements ▲(CN 1-Aug-2023)

Procedure for content uniformity

Solution A, Solution B, Mobile phase, and System suitability: Proceed as directed in Dissolution Test 1.

Standard solution: 26.4 µg/mL of USP Montelukast Dicyclohexylamine RS in methanol

Sample solution: Nominally 0.02 mg/mL of montelukast prepared as follows. Transfer the contents of one packet to a suitable volumetric flask, add 66% of the flask volume of methanol, shake well, and sonicate for 15 min with occasional shaking. Cool to room temperature, dilute with methanol to volume, and mix well. Pass a portion of the resulting solution through a suitable filter of 0.45-µm pore size or centrifuge to obtain a clear solution.

Chromatographic system: Proceed as directed in Dissolution Test 1, except use an Injection volume of 5 µL.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of montelukast (C₃₅H₃₆CINO₃S) in the packet taken:

                         Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) ×100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Montelukast Dicyclohexylamine RS in the Standard solution (mg/mL)

C_U = nominal concentration of montelukast in the Sample solution (mg/mL)

M_r1 = molecular weight of montelukast, 586.18

M_r2 = molecular weight of montelukast dicyclohexylamine, 767.50 

^▲_{▲(CN 1-Aug-2023)}

5 IMPURITIES

ORGANIC IMPURITIES

Diluent, Solution A, Solution B, Mobile phase, Standard solution, System suitability solution, Sensitivity solution, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual degradation product in the portion of Oral Granules taken:

                         Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) ×100

r_U = peak response of any individual degradation product from the Sample solution

r_S = peak response of montelukast from the Standard solution

C_S = concentration of USP Montelukast Dicyclohexylamine RS in the Standard solution (mg/mL)

C_U = nominal concentration of montelukast in the Sample solution (mg/mL) 

M_r1 = molecular weight of montelukast, 586.18

M_r2 = molecular weight of montelukast dicyclohexylamine, 767.50 

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. Disregard any peak with an area less than that of the Sensitivity solution.

Table 2

^a These two impurities are not resolved by the method and need to be integrated together to determine conformance.

^b [1-[[[1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl] phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl sulfinyl]methyl]cyclopropyl acetic acid.

^c (E)-1-(3-[2-(7-Chloroquinolin-2-yl)vinyl]phenyl)-3-[2-(2-hydroxypropan-2-yl)phenyl] propan-1-one.

^d [1-[[[(1R)-1-[3-[(Z)-2-(7-Chloroquinolin-2-yl)ethenyl)phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl sulfanyl]methyl]cyclopropyl acetic acid.

^e This is a process impurity and is included in the table for identification only. This impurity is controlled in the drug substance. It is not to be reported for the drug product and should not be included in the total impurities.

^f [1-[[[(1R)-3-(2-Acetylphenyl)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl]propyl sulfanyl]methyl]cyclopropyl acetic acid.

^g (1-{[(R)-1-(3-[(R)-1-([1-(Carboxymethyl)cyclopropyl methylthio)-2-(7-chloroquinolin-2-yl)ethyl]phenyl)-3-[2-(2-hydroxypгopan-2-yl)phenyl]propylthio]methylcyclopropyl)acetic acid.

^h (1-[(R)-1-(3-[(S)-1-([1-(Carboxymethyl)cyclopropyl methylthio)-2-(7-chloroquinolin-2-yl)ethyl]phenyl)-3-[2-(2-hydroxypropan-2-yl)phenyl]propylthio]methylcyclopropyl)acetic acid.

ⁱ [1-[[[(1R)-1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl)-3-[2-(1-methylethenyl)phenyl]propylsulfanyl]methyl]cyclopropyl acetic acid.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers, protected from light. Store at controlled room temperature.

LABELING: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used.

USP REFERENCE STANDARDS (11).

USP Montelukast Dicyclohexylamine RS

C₃₅H₃₆CINO₃S · C₁₂H₂₃N          767.50